NT-proBNP and changes in cognition and global brain structure: The Rotterdam Study.

OBJECTIVE: To investigate the association between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and changes in cognition and global brain structure. METHODS: In the Rotterdam Study, baseline NT-proBNP was assessed at baseline from 1997 to 2008. Between 1997 and 2016, participants without dementia or stroke at baseline (n = 9566) had repeated cognitive tests (every 3-6 years) for global cognitive function, executive cognitive function, fine manual dexterity, and memory. Magnetic resonance imaging of the brain was performed repeatedly at re-examination visits between 2005 and 2015 for 2607 participants to obtain brain volumes, focal brain lesions, and white matter microstructural integrity as measures of brain structure. RESULTS: Among 9566 participants (mean age 65.1 ± 9.8 years), 5444 (56.9%) were women, and repeated measures of cognition were performed during a median follow-up time of 5.5 (range 1.1-17.9) years, of whom 2607 participants completed at least one brain imaging scan. Higher levels of NT-proBNP were associated with a faster decline of scores in the global cognitive function (p value = 0.003) and the Word-Fluency test (p value = 0.003) but were not related to a steeper deterioration in brain volumes, global fractional anisotropy, and mean diffusivity, as indicators of white matter microstructural integrity, or focal brain lesions. CONCLUSIONS: Higher baseline NT-proBNP levels were associated with a faster decline in cognition; however, no association with global brain structure was found.

The association of coagulation and atrial fibrillation: a systematic review and meta-analysis.

AIMS: While atrial fibrillation (AF) is suggested to induce a prothrombotic state, increasing thrombotic risk, it is also hypothesized that coagulation underlies AF onset. However, conclusive evidence is lacking. With this systematic review and meta-analysis, we aimed to summarize and combine the evidence on the associations between coagulation factors with AF in both longitudinal and cross-sectional studies. METHODS AND RESULTS: We systematically searched for longitudinal cohort and cross-sectional studies investigating AF and thrombosis. For longitudinal studies, pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. For cross-sectional studies, we determined pooled standardized mean differences (SMDs) and 95% CIs. A total of 17 longitudinal and 44 cross-sectional studies were included. In longitudinal studies, we found significant associations between fibrinogen (HR 1.05, 95% CI 1.00-1.10), plasminogen activator inhibitor 1 (PAI-1) (HR 1.06, 95% CI 1.00-1.12), and D-dimer (HR 1.10, 95% CI 1.02-1.19) and AF incidence. In cross-sectional studies, we found significantly increased levels of fibrinogen (SMD 0.47, 95% CI 0.20-0,74), von Willebrand factor (SMD 0.96, 95% CI 0.28-1.66), P-selectin (SMD 0.31, 95% CI 0.08-0.54), ß-thromboglobulin (SMD 0.82, 95% CI 0.61-1.04), Platelet Factor 4 (SMD 0.42, 95% CI 0.12-0.7), PAI-1 (1.73, 95% CI 0.26-3.19), and D-dimer (SMD 1.74, 95% CI 0.36-3.11) in AF patients, as opposed to controls. CONCLUSION: These findings suggest that higher levels of coagulation factors are associated with prevalent and incident AF. These associations are most pronounced with prevalent AF in cross-sectional studies. Limited evidence from longitudinal studies suggests a prothrombotic state underlying AF development.

Autoimmune diseases and new-onset atrial fibrillation: a UK Biobank study.

AIMS: The underlying mechanisms of atrial fibrillation (AF) are largely unknown. Inflammation may underlie atrial remodelling. Autoimmune diseases, related to increased systemic inflammation, may therefore be associated with new-onset AF. METHODS AND RESULTS: Participants from the population-based UK Biobank were screened for rheumatic fever, gastrointestinal autoimmune diseases, autoimmune diseases targeting the musculoskeletal system and connective tissues, and neurological autoimmune diseases. Between 2006 and 2022, participants were followed for incident AF. Cox proportional hazards regression analyses were performed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to quantify associations. 494 072 participants free from AF were included (median age 58.0 years, 54.8% women). After a median of 12.8 years, 27 194 (5.5%) participants were diagnosed with new-onset AF. Rheumatic fever without heart involvement (HR, 95% CI: 1.47, 1.26-1.72), Crohn's disease (1.23, 1.05-1.45), ulcerative colitis (1.17, 1.06-1.31), rheumatoid arthritis (1.39, 1.28-1.51), polyarteritis nodosa (1.82, 1.04-3.09), systemic lupus erythematosus (1.82, 1.41-2.35), and systemic sclerosis (2.32, 1.57-3.44) were associated with a larger AF risk. In sex-stratified analyses, rheumatic fever without heart involvement, multiple sclerosis, Crohn's disease, seropositive rheumatoid arthritis, psoriatic and enteropathic arthropathies, systemic sclerosis and ankylosing spondylitis were associated with larger AF risk in women, whereas only men showed a larger AF risk associated with ulcerative colitis. CONCLUSIONS: Various autoimmune diseases are associated with new-onset AF, more distinct in women. Our findings elaborate on the pathophysiological differences in autoimmunity and AF risk between men and women.

Electrocardiographic parameters and the risk of new-onset atrial fibrillation in the general population: the Rotterdam Study.

AIMS: We aimed to assess the (shape of the) association and sex differences in the link between electrocardiographic parameters and new-onset atrial fibrillation (AF). METHODS AND RESULTS: A total of 12 212 participants free of AF at baseline from the population-based Rotterdam Study were included. Up to five repeated measurements of electrocardiographic parameters including PR, QRS, QT, QT corrected for heart rate (QTc), JT, RR interval, and heart rate were assessed at baseline and follow-up examinations. Cox proportional hazards- and joint models, adjusted for cardiovascular risk factors, were used to determine the (shape of the) association between baseline and longitudinal electrocardiographic parameters with new-onset AF. Additionally, we evaluated potential sex differences. During a median follow-up of 9.3 years, 1282 incident AF cases occurred among 12 212 participants (mean age 64.9 years, 58.2% women). Penalized cubic splines revealed that associations between baseline electrocardiographic measures and risk of new-onset AF were generally U- and N-shaped. Sex differences in terms of the shape of the various associations were most apparent for baseline PR, QT, QTc, RR interval, and heart rate in relation to new-onset AF. Longitudinal measures of higher PR interval [fully adjusted hazard ratio (HR), 95% confidence interval (CI), 1.43, 1.02-2.04, P = 0.0393] and higher QTc interval (fully adjusted HR, 95% CI, 5.23, 2.18-12.45, P = 0.0002) were significantly associated with new-onset AF, in particular in men. CONCLUSION: Associations of baseline electrocardiographic measures and risk of new-onset AF were mostly U- and N-shaped. Longitudinal electrocardiographic measures of PR and QTc interval were significantly associated with new-onset AF, in particular among men.

Heart rate variability is associated with left ventricular systolic, diastolic function and incident heart failure in the general population.

BACKGROUND: HRV has mostly shown associations with systolic dysfunction and more recently, with diastolic dysfunction in Heart failure (HF) patients. But the role of sympathetic nervous system in changes of left ventricular (LV) systolic and diastolic function and new-onset HF has not been extensively studied. METHODS: Among 3157 men and 4405 women free of HF and atrial fibrillation retrospectively included from the population-based Rotterdam Study, we used linear mixed models to examine associations of RR-interval differences and standard deviation of RR-intervals corrected for heart rate (RMSSDc and SDNNc) with longitudinal changes of LV ejection fraction (LVEF), E/A ratio, left atrial (LA) diameter, E/e' ratio. Afterwards, using cox regressions, we examined their association with new-onset HF. RESULTS: Mean (SD) age was 65 (9.95) in men and 65.7 (10.2) in women. Every unit increase in log RMSSDc was accompanied by 0.75% (95%CI:-1.11%;-0.39%) and 0.31% (- 0.60%;-0.01%) lower LVEF among men and women each year, respectively. Higher log RMSSDc was linked to 0.03 (- 0.04;-0.01) and 0.02 (- 0.03;-0.003) lower E/A and also - 1.76 (- 2.77;- 0.75) and - 1.18 (- 1.99;-0.38) lower LVM index in both sexes and 0.72 mm (95% CI: - 1.20;-0.25) smaller LA diameters in women. The associations with LVEF in women diminished after excluding HF cases during the first 3 years of follow-up. During a median follow-up of 8.7 years, hazard ratios (95%CI) for incident HF were 1.34 (1.08;1.65) for log RMSSDc in men and 1.15 (0.93;1.42) in women. SDNNc showed similar associations. CONCLUSIONS: Indices of HRV were associated with worse systolic function in men but mainly with improvement in LA size in women. Higher HRV was associated with higher risk of new-onset HF in men. Our findings highlight potential sex differences in autonomic function underlying cardiac dysfunction and heart failure in the general population.

Imaging-based body fat depots and new-onset atrial fibrillation in general population: a prospective cohort study.

BACKGROUND: Obesity is a well-established risk factor for atrial fibrillation (AF). Whether body fat depots differentially associate with AF development remains unknown. METHODS: In the prospective population-based Rotterdam Study, body composition was assessed using dual-energy X-ray absorptiometry (DXA) and liver and epicardial fat using computed tomography (CT). A body composition score was constructed by adding tertile scores of each fat depot. Principal component analysis was conducted to identify potential body fat distribution patterns. Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals (HR; 95% CI) per 1-standard deviation increase in corresponding fat depots to enable comparisons. RESULTS: Over a median follow-up of 9.6 and 8.6 years, 395 (11.4%) and 172 (8.0%) AF cases were ascertained in the DXA and the CT analyses, respectively. After adjustments for cardiovascular risk factors, absolute fat mass (HR; 95% CI 1.33; 1.05-1.68), gynoid fat mass (HR; 95% CI 1.36; 1.12-1.65), epicardial fat mass (HR; 95% CI 1.27; 1.09-1.48), and android-to-gynoid fat ratio (HR; 95% CI 0.81; 0.70-0.94) were independently associated with new-onset AF. After further adjustment for lean mass, associations between fat mass (HR; 95% CI 1.17; 1.04-1.32), gynoid fat mass (HR; 95% CI 1.21; 1.08-1.37), and android-to-gynoid fat ratio (HR; 95% CI 0.84; 0.72-0.97) remained statistically significant. Larger body fat score was associated with a higher AF risk (HR; 95% CI 1.10; 1.02-1.20). Borderline significant association was found between a subcutaneous fat predominant pattern with AF onset (HR; 95% CI 1.21; 0.98-1.49). CONCLUSIONS: Various body fat depots were associated with new-onset AF. Total fat mass and gynoid fat mass were independently associated with AF after adjustment for body size. The inverse association between android-to-gynoid fat ratio with AF presents a novel finding. A significant dose-response relationship between body fat accumulation and AF was observed. Our results underscore the predominant role of subcutaneous fat on AF development among a middle-aged and elderly population. Associations betw2een body fat depots, fat distribution and new-onset atrial fibrillation. ABBREVIATIONS: AF, atrial fibrillation.

Burden of cardiometabolic disorders and lifetime risk of new-onset atrial fibrillation among men and women: the Rotterdam Study.

AIMS: To examine the association between the burden of cardiometabolic disorders with new-onset AF and lifetime risk of AF incidence among men and women. METHODS: 4,101 men and 5,421 women free of AF at baseline (1996 to 2008) from the population-based Rotterdam Study were included. Sex-specific Cox proportional hazards regression models were used to assess the association between the burden of cardiometabolic disorders and risk of new-onset AF. Remaining lifetime risk for AF was estimated at index ages of 55, 65, and 75 years up to age 108. RESULTS: Mean age at baseline was 65.5 ± 9.4 years. Median follow-up time was 12.8 years. In the fully adjusted model, a stronger association was found between larger burden of cardiometabolic disorders and incident AF among women [hazard ratio (HR): 1.33 and 95% conference interval (CI): 1.22-1.46], compared to men [1.18 (1.08-1.29)] (P for sex-interaction <0.05). The lifetime risk for AF significantly increased with the number of cardiometabolic disorders among both sexes. At an index age of 55 years, the lifetime risks (95% CIs) for AF were 27.1% (20.8-33.4), 26.5% (22.8-30.5), 29.9% (26.7-33.2), 30.8% (25.7-35.8), and 33.3% (23.1-43.6) among men, for 0, 1, 2, 3, and ≥4 comorbid cardiometabolic disorders. Corresponding risks were15.8% (10.5-21.2), 23.0% (19.8-26.2), 29.7% (26.8-32.6), 26.2% (20.8-31.6), and 34.2% (17.3-51.1) among women. CONCLUSIONS: We observed a significant combined impact of cardiometabolic disorders on AF risk, in particular among women. Participants with cardiometabolic multimorbidity had a significantly higher lifetime risk of AF, especially at a young index age.

The present study examined the association between the burden of cardiometabolic disorders with new-onset atrial fibrillation and lifetime risk of atrial fibrillation incidence among 4101 men and 5421 women from the Rotterdam Study cohort. We observed a significant combined impact of cardiometabolic disorders on atrial fibrillation risk, in particular among women. Participants with cardiometabolic multimorbidity had a significantly higher lifetime risk of atrial fibrillation, especially at a young index age. A stronger association was found between larger burden of cardiometabolic disorders and incident atrial fibrillation among women [hazard ratio: 1.33 and 95% conference interval: 1.22-1.46], compared to men [1.18 (1.08-1.29)] (P for sex-interaction <0.05). Among participants aged 55 years or older, the lifetime risk of atrial fibrillation was 25.2% among healthy men and 16.3% among healthy women. Individuals with cardiometabolic multimorbidity exhibited a markedly escalated lifetime risk of atrial fibrillation, particularly evident at a younger age.

Atrial fibrillation patterns and their cardiovascular risk profiles in the general population: the Rotterdam study.

BACKGROUND: Clinical guidelines categorize atrial fibrillation (AF) based on the temporality of AF events. Due to its dependence on event duration, this classification is not applicable to population-based cohort settings. We aimed to develop a simple and standardized method to classify AF patterns at population level. Additionally, we compared the longitudinal trajectories of cardiovascular risk factors preceding the AF patterns, and between men and women. METHODS: Between 1990 and 2014, participants from the population-based Rotterdam study were followed for AF status, and categorized into 'single-documented AF episode', 'multiple-documented AF episodes', or 'long-standing persistent AF'. Using repeated measurements we created linear mixed-effects models to assess the longitudinal evolution of risk factors prior to AF diagnosis. RESULTS: We included 14,061 participants (59.1% women, mean age 65.4 ± 10.2 years). After a median follow-up of 9.4 years (interquartile range 8.27), 1,137 (8.1%) participants were categorized as 'single-documented AF episode', 208 (1.5%) as 'multiple-documented AF episodes', and 57 (0.4%) as 'long-standing persistent AF'. In men, we found poorer trajectories of weight and waist circumference preceding 'long-standing persistent AF' as compared to the other patterns. In women, we found worse trajectories of all risk factors between 'long-standing persistent AF' and the other patterns. CONCLUSION: We developed a standardized method to classify AF patterns in the general population. Participants categorized as 'long-standing persistent AF' showed poorer trajectories of cardiovascular risk factors prior to AF diagnosis, as compared to the other patterns. Our findings highlight sex differences in AF pathophysiology and provide insight into possible risk factors of AF patterns.

Heart rate variability and atrial fibrillation in the general population: a longitudinal and Mendelian randomization study.

BACKGROUND: Sex differences and causality of the association between heart rate variability (HRV) and atrial fibrillation (AF) in the general population remain unclear. METHODS: 12,334 participants free of AF from the population-based Rotterdam Study were included. Measures of HRV including the standard deviation of normal RR intervals (SDNN), SDNN corrected for heart rate (SDNNc), RR interval differences (RMSSD), RMSSD corrected for heart rate (RMSSDc), and heart rate were assessed at baseline and follow-up examinations. Joint models, adjusted for cardiovascular risk factors, were used to determine the association between longitudinal measures of HRV with new-onset AF. Genetic variants for HRV were used as instrumental variables in a Mendelian randomization (MR) analysis using genome-wide association studies (GWAS) summary-level data. RESULTS: During a median follow-up of 9.4 years, 1302 incident AF cases occurred among 12,334 participants (mean age 64.8 years, 58.3% women). In joint models, higher SDNN (fully-adjusted hazard ratio (HR), 95% confidence interval (CI) 1.24, 1.04-1.47, p = 0.0213), and higher RMSSD (fully-adjusted HR, 95% CI 1.33, 1.13-1.54, p = 0.0010) were significantly associated with new-onset AF. Sex-stratified analyses showed that the associations were mostly prominent among women. In MR analyses, a genetically determined increase in SDNN (odds ratio (OR), 95% CI 1.60, 1.27-2.02, p = 8.36 × 10-05), and RMSSD (OR, 95% CI 1.56, 1.31-1.86, p = 6.32 × 10-07) were significantly associated with an increased odds of AF. CONCLUSION: Longitudinal measures of uncorrected HRV were significantly associated with new-onset AF, especially among women. MR analyses supported the causal relationship between uncorrected measures of HRV with AF. Our findings indicate that measures to modulate HRV might prevent AF in the general population, in particular in women. AF; atrial fibrillation, GWAS; genome-wide association study, IVW; inverse variance weighted, MR; Mendelian randomization, MR-PRESSO; MR-egger and mendelian randomization pleiotropy residual sum and outlier, RMSSD; root mean square of successive RR interval differences, RMSSDc; root mean square of successive RR interval differences corrected for heart rate, SDNN; standard deviation of normal to normal RR intervals, SDNNc; standard deviation of normal to normal RR intervals corrected for heart rate, WME; weighted median estimator. aRotterdam Study n=12,334 bHRV GWAS n=53,174 cAF GWAS n=1,030,836.

Immunothrombosis and new-onset atrial fibrillation in the general population: the Rotterdam Study.

BACKGROUND: Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia. The etiology underlying AF is still largely unknown. At the intersection of the innate immune system and hemostasis, immunothrombosis may be a possible cause of atrial remodeling, and therefore be an underlying cause of AF. METHODS: From 1990 to 2014, we followed participants aged 55 and over, free from AF at inclusion. Immunothrombosis factors fibrinogen, von Willebrand factor, ADAMTS13, and neutrophil extracellular traps (NETs) levels were measured at baseline. Participants were followed until either onset of AF, loss-to-follow-up, or reaching the end-date of 01-01-2014. Cox proportional hazard modelling was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for cardiovascular risk factors. RESULTS: We followed 6174 participants (mean age 69.1 years, 57% women) for a median follow-up time of 12.8 years. 364 men (13.7%, incidence rate 13.0/1000 person-years) and 365 women (10.4%, incidence rate 8.9/1000 person-years) developed AF. We found no significant association between markers of immunothrombosis and new-onset AF after adjusting for cardiovascular risk factors [HR 1.00 (95% CI 0.93-1.08) for fibrinogen, 1.04 (0.97-1.12) for von Willebrand factor, 1.00 (1.00-1.01) for ADAMTS13, and 1.01 (0.94-1.09) for NETs]. In addition, we found no differences in associations between men and women. CONCLUSION: We found no associations between markers of immunothrombosis and new-onset AF in the general population. Inflammation and immunothrombosis may be associated with AF through other cardiovascular risk factors or predisposing conditions of AF. Our findings challenge the added value of biomarkers in AF risk prediction.

Longitudinal Anthropometric Measures and Risk of New-Onset Atrial Fibrillation Among Community-Dwelling Men and Women.

OBJECTIVE: To assess the sex-specific evolution of various anthropometric measures and the association of their longitudinal trajectories with new-onset atrial fibrillation (AF). METHODS: Among 5266 men and 7218 women free of AF at baseline from the prospective population-based Rotterdam Study, each anthropometric measure was measured 1 to 5 times from 1989 to 2014. Anthropometric measures were standardized to obtain hazard ratios per 1 SD increase to enable comparison. Joint models were used to assess the longitudinal association between anthropometric measures and incident AF. Use of the joint models is a preferred method for simultaneous analyses of repeated measurements and survival data for conferring less biased estimates. RESULTS: Mean (SD) age was 63.9 (8.9) years for men and 64.9 (9.8) years for women. Median follow-up time was 10.5 years. Longitudinal evolution of weight, height, waist circumference, hip circumference, and body mass index was associated with an increased risk of new-onset AF in both men and women. In joint models, larger height in men (hazard ratio [95% credible interval] per 1 SD, 1.27 [1.17 to 1.38]) and weight in women (1.24 [1.16 to 1.34]) showed the largest associations with AF. In joint models, waist to hip ratio was significantly associated with incident AF only in women (1.10 [1.03 to 1.18]). CONCLUSION: Considering the entire longitudinal trajectories in joint models, anthropometric measures were positively associated with an increased risk for new-onset AF among men and women in the general population. Increase in measure of central obesity showed a stronger association with increased risk of AF onset among women compared with men.

Sex-specific anthropometric and blood pressure trajectories and risk of incident atrial fibrillation: the Rotterdam Study.

AIMS: To investigate sex-specific longitudinal trajectories of various obesity-related measures and blood pressure at the population level and further assess the impact of these trajectories on new-onset atrial fibrillation (AF). METHODS AND RESULTS: Participants with ≥2 repeated assessments for various risk factors from the population-based Rotterdam Study were included. Latent class linear mixed models were fitted to identify the potential classes. Cox proportional-hazard models were used to assess the association between risk factors' trajectories and the risk of new-onset AF, with the most favourable trajectory as reference. Among 7367 participants (mean baseline age: 73 years, 58.8% women), after a median follow-up time of 8.9 years (interquartile range: 5.3-10.4), 769 (11.4%) participants developed new-onset AF. After adjustments for cardiovascular risk factors, persistent-increasing body mass index (BMI) trajectory carried a higher risk for AF [hazard ratio, 95% confidence interval: (1.39; 1.05-1.85) in men and (1.60; 1.19-2.15) in women], compared with the lower-and-stable BMI trajectory. Trajectories of elevated-and-stable waist circumference (WC) in women (1.53; 1.09-2.15) and elevated-and-stable hip circumference (HC) in men (1.83; 1.11-3.03) were associated with incident AF. For systolic blood pressure (SBP), the initially hypertensive trajectory carried the largest risk for AF among women (1.79; 1.21-2.65) and men (1.82; 1.13-2.95). Diastolic blood pressure trajectories were significantly associated with AF risk among women but not among men. CONCLUSION: Longitudinal trajectories of weight, BMI, WC, HC, and SBP were associated with new-onset AF in both men and women. Diastolic blood pressure trajectories were additionally associated with AF in women. Our results highlight the importance of assessing long-term exposure to risk factors for AF prevention among men and women.